Huntington's disease (HD) is a neurodegenerative disorder marked by debilitating motor, cognitive, and emotional symptoms. It is caused by a dominantly inherited CAG triplet repeat expansion in the Huntingtin (HTT) gene, which gives rise to HD pathology both via toxic gains of function of the mutant HTT protein and interference with the critical functions of wild-type HTT. This proposal seeks to better elucidate how the expression of the wild-type human HTT gene is regulated by a hominid-specific long noncoding RNA (lncRNA) that has been linked to autism, highlighting its potential importance in the brain. Preliminary data indicate that the lncRNA is expressed in the human brain in a similar regional enrichment pattern as HTT mRNA, and that it increases human HTT expression in transgenic mice expressing both human genes. Cell culture assays will investigate whether an intronic transposable element in the HTT gene is necessary and sufficient to confer its regulation by the lncRNA, and to identify the chromatin remodeling processes that are recruited by the lncRNA to increase HTT transcription. The human lncRNA and HTT genes will then be expressed in transgenic mice to reconstitute the genetic regulatory system. Experiments in these mice will examine the effects of lncRNA expression on molecular, cellular, and behavioral processes that are enhanced by wild-type HTT and impaired in HD models. Specifically, neuronal gene transcription, apoptosis, vesicle motility, anxiety-like behaviors, and cognitive function in the Morris water maze will be assayed. Illuminating this novel, hominid-specific mechanism controlling the expression of wild-type HTT will provide a more thorough understanding of the normal functions that HD pathology impinges upon, and may thereby advance the development of improved therapies.